Somatostatin and insulin secretion due to common mechanisms by a new hypoglycemic agent, A-4166, in perfused rat pancreas

Shoji Fujitani, Takao Ikenoue, Megumi Akiyoshi, Toshio Maki, Toshihiko Yada

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

N-[(trans-4-isopropylcyclohexyl)-carbonyl]-D-phenylalanine (A-4166) is a nonsulfonylurea hypoglycemic agent that decreases blood glucose levels in nondiabetic and diabetic animals. In the present study, we attempted to determine the effect of A-4166 on hormone secretion from the in vitro- perfused rat pancreas and to examine the underlying secretory mechanisms. In the presence of basal glucose (3 mmol/L), A-4166 markedly stimulated insulin and somatostatin release in a concentration-dependent manner over 0.03 to 3 mmol/L. A sulfonylurea, tolbutamide, also stimulated insulin and somatostatin release. A-4166 and tolbutamide elevated the level of glucagon release; however, the change tacked a clear concentration-dependent property. A-4166 at 0.3 mmol/L and tolbutamide at 3 mmol/L exhibited maximal stimulation of insulin release to a similar extent, indicating that A-4166 is one log-order more potent than and as effective as tolbutamide. By contrast, A-4166 stimulated somatostatin release to a threefold greater extent than tolbutamide. A-4166 evoked an increase in the cytosolic free-Ca2+ concentration ([Ca2+](i)) in rat pancreatic β cells. [Ca2+](i) and insulin secretory responses to A-4166 were inhibited by nitrendipine (NTD), a blocker of the L-type Ca2+ channel, and by diazoxide (DAZ), an opener of the adenosine triphosphate (ATP)-sensitive K+ channel. Furthermore, A-4166- stimulated somatostatin release was also inhibited by NTD and by DAZ. The results indicate that A-4166 and tolbutamide stimulate the release of insulin and somatostatin, and that A-4166 is much more effective than tolbutamide in releasing somatostatin, a hormone that attenuates hyperglycemia under certain circumstances. It is concluded that A-4166-induced insulin release is mediated by an increase in [Ca2+](i) in β cells. An inhibition of ATP- sensitive K+ channels and a consequent activation of L-type Ca2+ channels appear to play a key role not only in insulin secretion from β cells, but also in somatostatin secretion from δ cells in response to A-4166.

Original languageEnglish
Pages (from-to)184-189
Number of pages6
JournalMetabolism: Clinical and Experimental
Volume45
Issue number2
DOIs
Publication statusPublished - 1996
Externally publishedYes

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

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